Despite the availability of effective vaccines and antiviral therapies, hepatitis B is still a major global health problem, with one-third of all people on the planet having been at some time infected with the hepatitis B virus (HBV). In 2016, there are currently more than 240 million people with chronic hepatitis B, which leads to more than 780,000 deaths per year following development of liver disease, such as cirrhosis, liver cancer, or other complications. The therapeutic options for the patients with chronic hepatitis B include two forms of interferon-α (IFN-α) as immune system modulators and nucleos(t)ide analogues. IFN-α therapy is effective for up to 60% of patients but results in complete cures in only 7% and also is associated with a high rate of adverse side effects.
The hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA virus. The virus particle is composed of a lipid enveloped studded with surface protein (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core.
One of the classic hallmarks of chronic hepatitis B is the high levels of hepatitis B virus surface antigen (HBsAg) in the serum of patients, which may reach 400 μg/mL (0.4% of total serum protein). The antigenemia resulting from production of subviral particles is thought to play an important role in suppressing the HBV-specific immune response. In addition, recent reports have suggested that HBsAg acts directly on dendritic cells to limit cytokine production and adaptive immunity. Reduction of antigenemia with the experimental antiviral clevudine resulted in a partial restoration of virus-specific immune response. Thus, inhibitors of HBsAg secretion could potentially enable the therapeutic use of the HBV vaccine or be used as combination therapy with nucleos(t)ide drugs for the treatment of HBV infection.
WO/2015/113990 and WO/2016/107832 reported a class of HBsAg inhibitors for the treatment and prophylaxis of hepatitis b virus infection. The paper in J Med Chem. 2011, 54(16): 5660-5670 reported novel agents triazolo-pyrimidine derivatives as novel inhibitors of HBsAg secretion. Although those agents have made a significant contribution to the art, there is a continuing search in this field of art for improved pharmaceuticals.